Format

Send to

Choose Destination
PLoS Genet. 2015 Nov 2;11(11):e1005607. doi: 10.1371/journal.pgen.1005607. eCollection 2015 Nov.

Mapping of Craniofacial Traits in Outbred Mice Identifies Major Developmental Genes Involved in Shape Determination.

Author information

1
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, Plön, Germany.
2
Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.
3
Center for Musculoskeletal Research, University of Rochester, Rochester, New York, United States of America.
4
Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois, United States of America.

Abstract

The vertebrate cranium is a prime example of the high evolvability of complex traits. While evidence of genes and developmental pathways underlying craniofacial shape determination is accumulating, we are still far from understanding how such variation at the genetic level is translated into craniofacial shape variation. Here we used 3D geometric morphometrics to map genes involved in shape determination in a population of outbred mice (Carworth Farms White, or CFW). We defined shape traits via principal component analysis of 3D skull and mandible measurements. We mapped genetic loci associated with shape traits at ~80,000 candidate single nucleotide polymorphisms in ~700 male mice. We found that craniofacial shape and size are highly heritable, polygenic traits. Despite the polygenic nature of the traits, we identified 17 loci that explain variation in skull shape, and 8 loci associated with variation in mandible shape. Together, the associated variants account for 11.4% of skull and 4.4% of mandible shape variation, however, the total additive genetic variance associated with phenotypic variation was estimated in ~45%. Candidate genes within the associated loci have known roles in craniofacial development; this includes 6 transcription factors and several regulators of bone developmental pathways. One gene, Mn1, has an unusually large effect on shape variation in our study. A knockout of this gene was previously shown to affect negatively the development of membranous bones of the cranial skeleton, and evolutionary analysis shows that the gene has arisen at the base of the bony vertebrates (Eutelostomi), where the ossified head first appeared. Therefore, Mn1 emerges as a key gene for both skull formation and within-population shape variation. Our study shows that it is possible to identify important developmental genes through genome-wide mapping of high-dimensional shape features in an outbred population.

PMID:
26523602
PMCID:
PMC4629907
DOI:
10.1371/journal.pgen.1005607
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center